Processes for the preparation of oxo-oxazoline or alloamino acid derivatives

ABSTRACT

A method for producing a compound represented by the general formula (I-A) or the general formula (I-B), comprising the following step: 
                 
 
wherein R 1  is an optionally substituted lower alkyl, and the like; R 2  is a lower alkyl or an optionally substituted aralkyl, and the like; R 3  is a lower alkyl, characterized in that a compound represented by the general formula (II-A) or the general formula (II-B) is treated with thionyl chloride.

This application is a divisional application of U.S. application Ser.No. 10/229,819, filed Aug. 27, 2002, now U.S. Pat. No. 6,747,157 whichis a divisional application of U.S. application Ser. No. 10/070,974,filed Jun. 19, 2002, now U.S. Pat. No. 6,541,641, which is a 35 U.S.C. §371 National Stage application of International ApplicationPCT/JP00/05753, filed Aug. 25, 2000, which designates the United Statesof America.

TECHNICAL FIELD

The present invention relates to a method for producing oxo-oxazolinederivatives using a simple and inexpensive method.

BACKGROUND ART

Oxo-oxazoline derivatives are critical intermediates for compounds(WO98/08867) which are TRH (thyrotropin releasing hormone) derivativesrepresented by the following general formula (VIII):

wherein R^(A) is a hydrogen atom or optionally substituted lower alkyl:Y is an optionally substituted alkyl.

Further, compounds represented by the following general formulas(III-A), (III-B), (IV-A), or (IV-B):

wherein R¹ is an optionally substituted lower alkyl, an optionallysubstituted aryl, an alkynyl, or an optionally substituted heteroaryl,and derivatives thereof, are useful as tools for combinatorialchemistry.

Conventionally, as a method for producing oxo-oxazoline derivativeshaving a lower alkyloxycarbonyl group or a carboxyl group, a method ofcyclizing a starting material while retaining its stereochemistry, and amethod using cyclization reaction without reference to stereoselectivityare known.

An example of the method of cyclizing a starting material whileretaining its stereochemistry is the following:

(Tetrahedron, 48, 2507, 1992). In this reaction, L-allo-threonine usedas a starting material is allowed to react with phosgene and potassiumhydroxide in toluene at 0° C. for one hour, thereby obtaining a cyclizedproduct which retains its stereochemisty. Unfortunately, this methodencounters a problem in industrialization since the method employsL-allo-threonine which is more expensive than its natural type, andphosgene which is toxic to the human body.

An example of the cyclization method without reference tostereoselectivity is the following:

(Japanese Laid-Open Publication No. 60-34955). In this reaction, astarting material is allowed to react with potassium carbonate in waterat 60° C. for 1.5 hours to obtain a cyclized product. It is believedthat the stereochemistry of the material is maintained in view of themechanism of this method. Therefore, it is considered thatallo-threonine needs to be used as a starting material in order toobtain a cis-form cyclized product.

Although a resultant cyclized product is an oxo-oxazoline derivativewhich does not have a lower alkyloxycarbonyl group or a carboxyl group,the following method is known:

(Bull. Chem. Soc. Japan., 44, 2515, 1971). In this reaction, a startingmaterial is allowed to react in thionyl chloride at 60° C. for 24 hourswithout solvent, thereby obtaining a cyclized product at a yield of 65%.In this method, similar to the method of the present invention, theposition of an ethyl group is inverted after the reaction. However, thestarting material is not an amino acid derivative, and the relationshipbetween the amino group and the hydroxyl group of the starting materialis different from that of a starting material used in the method of thepresent invention. Moreover, since the reaction is conducted in thionylchloride, the yield is as low as 65%.

Similar to the method of the present invention, a cyclization reactionwith inversion is known:

(Heterocycl. Commun., 2, 55, 1996). An example in which trifluoroaceticanydride is used in the first step is disclosed. Although in the methodof the present invention, the yield of a cyclization reaction is as highas 83%, the yield of the cyclization reaction disclosed in theabove-described publication is as low as 40% in both a method usingtosyl chloride and a method using trifluoroacetic anydride. Moreover,the method of the present invention is superior in regard to simplicityof reaction.

DISCLOSURE OF THE INVENTION

The objective of the present invention is to provide a method forproducing oxo-oxazoline derivatives in a simple, inexpensive andstereoselective manner. The oxo-oxazoline derivatives are useful asintermediates for pharmaceuticals and tools for combinatorial chemistry.Moreover, the oxo-oxazoline derivatives in an open-circular form arealso useful as tools for combinatorial chemistry.

The inventors found a method for producing oxo-oxazoline derivatives ina stereoselective manner, which is suitable for large-scale synthesis.

That is, the present invention relates to

-   I) A method for the production of a compound represented by a    general formula (I-A) or a general formula (I-B), comprising the    step of treating a compound represented by a general formula (II-A)    or a general formula (II-B) with thionyl chloride as follows:    wherein R¹ is an optionally substituted lower alkyl, an optionally    substituted aryl, an alkynyl, or an optionally substituted    heteroaryl; R² is a lower alkyl, an optionally substituted aralkyl,    or an optionally substituted heteroarylalkyl; and R³ is a lower    alkyl.

More specifically, the present invention relates to following II) to X).

-   II) A method for the production according to I), wherein the    compound represented by the general formula (II-A) or the general    formula (II-B) is allowed to react with 1.0 to 5.0 equivalents of    thionyl chloride in a solvent of toluene, ethyl acetate,    cyclohexane, or acetonitrile at 30° C. to reflux temperature.-   III) A method for the production according to I), wherein the    compound represented by the general formula (II-A) or the general    formula (II-B) is allowed to react with 1.0 to 3.0 equivalents of    thionyl chloride in a solvent of toluene, ethyl acetate,    cyclohexane, or acetonitrile at 60° C. to 80° C.

IV) A method for the production of a compound represented by a generalformula (III-A) or a general formula (III-B), comprising the step ofsubjecting a compound represented by a general formula (I-A) or ageneral formula (I-B) obtained by a method according to any of I) toIII) to a hydrolysis as follows:

wherein R¹ and R³ are as described above.

-   V) A method for the production of a compound represented by a    general formula (IV-A) or a general formula (IV-B), comprising the    step of subjecting a compound represented by a general formula    (III-A) or a general formula (III-B) obtained by a method according    to IV) to a hydrolysis as follows:    wherein R¹ is as described above.-   VI) A method for the production of a compound represented by a    general formula (I-A) or a general formula (I-B), comprising the    step of protecting the amino group of a compound represented by a    general formula (V-A) or a general formula (V-B) with R²OC(═O)—,    wherein R² is as described above, esterifying the carboxyl group    thereof, and treating with thionyl chloride as follows:    wherein R¹ and R³ are as described above.-   VII) A method for production of a compound represented by a general    formula (VI):    wherein R¹ is as described above, and Y is an optionally substituted    alkyl, comprising the step of subjecting a compound represented by a    general formula (III-A) or a general formula (III-B) obtained by a    method according to IV) to a peptide bond formation.-   VIII) A method for the production according to IV), wherein R¹ is    phenyl, 5-imidazolyl, methyl, isopropyl, ethynyl, or 1-propynyl.-   IX) A method for the production according to IV), wherein R² is a    lower alkyl, an aralkyl, or a heteroarylalkyl.-   X) A method for the production according to IV), wherein R² is an    aralkyl.-   XI) A method for the production according to IV), wherein R¹ is    methyl and R² is benzyl.

“Halogen” as used herein refers to fluorine, chlorine, bromine, andiodine. Chlorine and bromine are preferable.

The term “lower alkyl” as herein used alone or in combination with otherwords comprises C₁-C₆ straight chained or branched alkyl. Examples ofthe lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, and t-butyl, and the like. Methyl and ethyl arepreferable.

“Alkynyl” as used herein comprises C₂-C₈ straight or branched chainmonovalent hydrocarbon group having one or two or more triple bonds. Thealkynyl may have a double bond. Examples of the alkynyl include ethynyl,1-propynyl, 2-propynyl, 6-heptynyl, 7-octynyl, and 8-nonyl, and thelike. Ethynyl and 1-propynyl are preferable.

The term “aryl” as herein used alone or in combination with other wordscomprises a monocyclic or condensed ring aromatic hydrocarbon. Examplesof the aryl include phenyl, 1-naphthyl, 2-naphthyl, anthryl, and thelike.

“Aralkyl” as used herein comprises the above-described “lower alkyl”substituted with the above-described “aryl” where the substitution maybe carried out at any possible position. Examples of the aralkyl includebenzyl, phenylethyl (e.g., 2-phenylethyl, and the like), phenylpropyl(e.g., 3-phenylpropyl, and the like), naphthylmethyl (e.g.,1-naphthylmethyl, 2-naphthylmethyl, and the like), and anthrylmethyl(e.g., 9-anthrylmethyl, and the like), and the like. Benzyl, and thelike are preferable.

“Heteroaryl” as used herein comprises a 5 to 6-membered aromatic ringincluding one or more atoms arbitrarily selected from oxygen atom,sulfur atom or nitrogen atom within the ring. Heteroaryl may be fusedwith cycloalkyl, aryl, or other heteroaryl at any possible position.Regardless whether the heteroaryl is monocyclic or fused cyclic, theheteroaryl can bind at any possible position.

Examples of the heteroaryl include pyrrolyl (e.g., 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl), furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g.,2-thienyl, 3-thienyl), imidazolyl (e.g., 4-imidazolyl, 5-imidazolyl),pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g.,3-isothiazolyl), isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g.,2-oxazolyl), thiazolyl (e.g., 2-thiazolyl), pyridyl (e.g., 2-pyridyl,3-pyridyl, 4-pyridyl), pyrazinyl (e.g., 2-pyrazinyl), pyrimidinyl (e.g.,2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl),tetrazolyl (e.g., 1H-tetrazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazolyl),thiadiazolyl (e.g., 1,3,4-thiadiazolyl), indolizinyl (e.g.,2-indolizinyl, 6-indolizinyl), isoindolyl (e.g., 2-isoindolyl), indolyl(e.g., 1-indolyl, 2-indolyl, 3-indolyl), indazolyl (e.g., 3-indazolyl),purinyl (e.g., 8-purinyl), quinolizinyl (e.g., 2-quinolizinyl),isoquinolyl (e.g., 3-isoquinolyl), quinolyl (e.g., 2-quinolyl,5-quinolyl), phthalazinyl (e.g., 1-phthalazinyl), naphthyridinyl (e.g.,2-naphthyridinyl), quinolanyl (e.g., 2-quinolanyl), quinazolinyl (e.g.,2-quinazolinyl), cinnolinyl (e.g., 3-cinnolinyl), pteridinyl (e.g.,2-pteridinyl), carbazolyl (e.g., 2-carbazolyl, 4-carbazolyl),phenanthridinyl (e.g., 2-phenanthridinyl, 3-phenanthridinyl), acridinyl(e.g., 1-acridinyl, 2-acridinyl), dibenzofuranyl (e.g.,1-dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (e.g.,2-benzimidazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), benzoxazolyl(e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl),benzisothiazolyl (e.g., 3-benzisothiazolyl), benzothiazolyl (e.g.,2-benzothiazolyl), benzofuryl (e.g., 3-benzofuryl), and benzothienyl(e.g., 2-benzothienyl). As “heteroaryl” of R¹, imidazolyl and the likeare preferable.

“Heteroarylalkyl” as used herein comprises the above-described “loweralkyl” substituted with the above-described “heteroaryl”, where such asubstitution may be carried out at any possible position.

“Optionally substituted lower alkyl” at R¹ as used herein comprises theabove-described “lower alkyl” which may have one or more substituents atany possible positions, such as hydroxy, alkyloxy (e.g., methoxy andethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogen (e.g.,fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g.,methyloxycarbonyl and. ethyloxycarbonyl), aryloxycarbonyl (e.g.,phenyloxycarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl,alkylcarbonyl, and the like. Preferable examples of the substituentinclude lower alkyloxy, halogen, and the like. Examples of the“optionally substituted lower alkyl” include methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, andtrifluoromethyl, and the like. An unsubstituted lower alkyl ispreferable.

“Optionally substituted alkyl” at Y as used herein comprises theabove-described “alkyl” which may have one or more substituents at anypossible positions, such as hydroxy, alkyloxy (e.g., methoxy andethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g.,fluorine, chlorine, bromine, and iodine), carboxy, carbamoyl,alkyloxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl),aryloxycarbonyl (e.g., phenyloxycarbonyl), nitro, cyano, SO_(p)R^(A) (pis an integer of 1 to 3, R^(A) is hydrogen or alkyl), PO(OH)₂ or P(O)OHwhich may be substituted with alkyl, substituted or unsubstituted amino(e.g., methylamino, dimethyl amino, and carbamoyl amino), optionallysubstituted aryl (e.g., phenyl and tolyl), optionally substitutedheteroaryl, optionally substituted nonaromatic heterocyclic group,aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, nonaromaticheterocyclic carbonyl, heterocyclic imino, hydrazino, hydroxyamino,alkyloxyamino, formyl, and the like. Examples of the “optionallysubstituted alkyl” include methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl,benzyl, hydroxymethyl, tert-butylcarbonyloxymethyl, morpholinomethyl,piperidinomethyl, N-methyl-1-piperazinylmethyl, ethylcarbonylmethyl, andmorpholinocarbonylmethyl, acetyloxymethyl, and the like. Anunsubstituted alkyl is preferable, particularly methyl.

“Optionally substituted aryl” as used herein comprises theabove-described “aryl” which may have one or more substituents at anypossible positions, such as hydroxy, alkyloxy (e.g., methoxy andethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g.,fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g.,methyloxycarbonyl and ethyloxycarbonyl), aryloxycarbonyl (e.g.,phenyloxycarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl,alkylcarbonyl, and the like. Preferable examples of the substituentinclude lower alkyloxy and halogen, and the like. Examples of the“optionally substituted aryl” include phenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, and the like. An unsubstituted aryl ispreferable.

“Optionally substituted heteroaryl” as used herein comprises theabove-described “heteroaryl” which may have one or more substituents atany possible positions, such as hydroxy, alkyloxy (e.g., methoxy andethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogen (e.g.,fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g.,methyloxycarbonyl and ethyloxycarbonyl), aryloxycarbonyl (e.g.,phenyloxycarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl,alkylcarbonyl, and the like. Preferable examples of the substituentsinclude lower alkyloxy, halogen, and the like. Examples of the“optionally substituted heteroaryl” include 2-chloroimidazole-5-yl,4-chloroimidazole-5-yl, and the like. An unsubstituted heteroaryl ispreferable.

“Optionally substituted aralkyl” as used herein comprises theabove-described “aralkyl” which may have one or more substituents at anypossible positions, such as hydroxy, alkyloxy (e.g., methoxy andethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), halogen (e.g.,fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g.,methyloxycarbonyl and ethyloxycarbonyl), aryloxycarbonyl (e.g.,phenyloxycarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl,alkylcarbonyl, and the like. Preferable examples of the substituentsinclude lower alkyloxy, halogen, and the like. Examples of the“optionally substituted aralkyl” include furyl, thienyl, pyridyl,5-chlorofuryl, 5-thienyl, 3-chloropyridyl, and the like. Anunsubstituted aralkyl is preferable.

BEST MODE FOR CARRYING OUT THE INVENTION

The production method of the present invention will be described indetail in which a starting material is one optically active substance.When the other material is used, similar reactions can be carried out.When a starting material has a substituent which is an obstacle to areaction in first to sixth steps shown below, the starting material maybe protected in advance in accordance with a method described inProtective Groups in Organic Synthesis, Theodora W Green (John Wiley &Sons), and the like, and deprotected in an appropriate stage.

wherein R¹, R², R³, and Y are as described above.

(First Step)

In the first step, R²OC(═O)-Hal, wherein Hal is halogen, [R²OC(═O)]₂O,and the like are caused to react with a compound represented by ageneral formula (V-A) to obtain a compound (VII-A) in which an aminogroup is protected by R²OC(═O)—. This step can be carried out inaccordance with a method described in Protective Groups in OrganicSynthesis, Theodora W Green (John Wiley & Sons), and the like.

For example, a compound represented by a general formula (V-A) is causedto react with 1.0 equivalent to 3.0 equivalents, preferably 1.0equivalent to 1.5 equivalents, of R²OC(═O)-Hal, wherein Hal is halogen,and 2.0 equivalents to 6.0 equivalents, preferably 2.0 equivalents to3.0 equivalents, of an organic base (e.g., triethylamine, and the like)or an inorganic base (e.g., sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate, sodium hydrogencarbonate,potassium hydrogencarbonate, and the like), in a mixed solvent, such aswater-toluene, water-dioxane, water-acetone, and the like, or a solvent,such as water, dioxane, and the like at −20° C. to 50° C., preferably 0°C. to 20° C. for 0.5 to 3 hours to obtain a compound represented by ageneral formula (VII-A).

In the above-described IV), “step of protecting an amino group withR²OC(═O)—” refers to this first step.

(Second Step)

In the second step, the carboxyl group of a compound represented by ageneral formula (VII-A) is esterified to obtain a compound representedby a general formula (II-A). This step can be carried out by a commonlyused esterification.

For example, a compound represented by the general formula (VII-A) isdissolved in a solvent, such as methanol, ethanol, isopropyl alcohol,and the like, and allowed to react with 1 equivalent to 5 equivalents,preferably 1 equivalent to 2 equivalents, of a halogenating agent, suchas thionyl chloride, hydrochloric acid, phosphorus oxychloride, and thelike, at −20° C. to 50° C., preferably 0° C. to 25° C., one hour to 24hours, preferably one hour to 3 hours to obtain a compound representedby a general formula (II-A).

In the above-described IV), “step of esterifying a carboxyl group”refers to this second step.

(Third Step)

The third step is a cyclization reaction in which the stereochemistry ofR¹ is reversed.

For example, a compound represented by a general formula (I-A) can beobtained in accordance with 1) to 3) described below. 1) a compoundrepresented by a general formula (II-A) is dissolved in a solvent, suchas toluene, ethyl acetate, cyclohexane, acetonitrile, and the like,preferably toluene. The amount of the solvent is preferably 1 V to 50 V,particularly 1 V to 10 V, where use of 1 ml of a solvent with respect to1 g of a starting material is referred to as 1 V. 2) 1.0 equivalent to20 equivalents, preferably 1.0 equivalent to 2.0 equivalents, of thionylchloride are added at 25° C. to 80° C., preferably 25° C. to 50° C.Thionyl chloride can be used as a solvent. 3) The reaction solution isstirred at 25° C. to 80° C., preferably 60° C. to 80° C., for 5 hours to48 hours, preferably 6 hours to 12 hours.

In this reaction, the closer the equivalent value of thionyl chloride isto 1.0 and the higher the “V” value of the amount of the solvent, theproportion of the cis-form of the intended compound was increased (theproportion of the trans-form was decreased).

The yield of the total compounds of cis-form and trans-form is notsubstantially affected by the equivalent value of thionyl chloride andthe amount of the solvent.

In the above-described IV), “step of treating with thionyl chloride”refers to this third step.

(Fourth Step)

In the fourth step, an ester compound represented by the general formula(I-A) is hydrolyzed to carboxylic acid. This step can be carried out bya commonly used hydrolysis.

For example, a compound represented by the general formula (I-A) isdissolved in a solvent, such as water, and the like, and 0.1 equivalentto 10 equivalents, preferably 1 equivalent to 5 equivalents, of acid(e.g., hydrochloric acid, sulfuric acid, and the like) are added to thesolution at 0° C. to 100° C., preferably 25° C. to 80° C. The resultantsolution is allowed to react at 25° C. to 100° C., preferably 50° C. to80° C. for 1 hour to 5 hours to obtain a compound represented by ageneral formula (III-A). This step can be carried out under basicconditions.

(Fifth Step)

In the fifth step, a compound represented by the general formula (III-A)is hydrolyzed to obtain allo-amino acid derivatives represented by ageneral formula (IV-A).

For example, a compound represented by the general formula (III-A) isdissolved in a solvent, such as water, and 0.1 equivalent to 20equivalents, preferably 1 equivalent to 10 equivalents, of acid (e.g.,hydrochloric acid, sulfuric acid, and the like) are added to thesolution at 0° C. to 100° C., preferably 25° C. to 80° C. The resultantsolution is allowed to react at 25° C. to 100° C., preferably 80° C. to100° C. for 1 hour to 48 hours to obtain a compound represented by thegeneral formula (IV-A).

(Sixth Step) (Peptide Bond Formation)

Three amino acid derivatives are subjected to two peptide bond formationto synthesize a compound (VI) (WO98/08867). A compound represented bythe general formula (I-A) obtained by the above-described method is usedto synthesize the compound (VI) in the following two methods (method Aand method B).

wherein R⁴ is the protecting group of a carboxyl group, R⁵ is theprotecting group of an amino group, and R¹ and Y are as described above.

Method A—First Step

The carboxyl group of 3-(4-thiazole)alanine synthesized in accordancewith a method described in Synth. Commun., 20, 22, 3507 (1990) and Chem.Pharm. Bull., 38, 1, 103 (1990), is protected as an ester, such asmethyl ester, benzyl ester, t-butyl ester, diphenylmethyl ester, and thelike, resulting in a compound represented by a general formula (VIII).This compound and a compound represented by the general formula (III-A)are subjected to a peptide bond formation.

When the carboxyl group is protected as diphenylmethyl ester, theprotecting reaction can be carried out as follows. 3-(4-thiazole)alanineis dissolved in a mixed solvent of an alcohol solvent, such as methanol,ethanol, and the like and a solvent, such as tetrahydrofuran, dioxane,and the like. 1 to 3 equivalents, preferably 1 to 2 equivalents, ofdiphenyl diazomethane are added to the solution at 0 to 50° C.,preferably 20 to 40° C. for 10 minutes to 1 hour, preferably 20 to 40minutes. The resultant solution is allowed to react at the sametemperature for 30 minutes to 3 hours, preferably 1 to 2 hours whilebeing stirred.

The peptide bond formation is described in “Peputido Gosei [PeptideSynthesis]” (Nobuo Izumiya, Maruzen), and the like, and can be carriedout by such a commonly used peptide bond formation method.

As commonly used peptide bond formation methods, a method employing acondensing agent, such as N,N-dicyclohexylcarbodiimide (DCC), and thelike, an azide method, an acid chloride method, an acid anhydridemethod, an active ester method, and the like. When a starting materialhas a substituent (amino, carboxy, hydroxyl, and the like) which is anobstacle to the peptide formation, the substituent can be protected inadvance in accordance with a method described in Protective Groups inOrganic Synthesis, Theodora W. Green (John Wiley & Sons), and the like,and the protecting group is removed at a desired stage.

A compound represented by the general formula (VIII) and a compoundrepresented by the general formula (III-A) are dissolved in a solvent,such as N,N-dimethylformamide, tetrahydrofuran, acetonitrile, and thelike. An N,N-dimethylformamide solution of a base, such astriethylamine, and the like, and dicyclohexylcarbodiimide (DCC), isadded to that solution at −10 to 10° C., preferably in ice bath.1-hydroxybenzotriazole may be added. The resultant solution is stirredat 10 to 50° C., preferably 20 to 30° C., for one hour to one day,preferably 5 to 10 hours, followed by typical subsequent processes.Thus, a compound represented by a general formula (IX) can be obtained.

Method A—Second Step

A deprotecting reaction can be carried out by a commonly useddeprotecting reaction (Protective Groups in Organic Synthesis, TheodoraW. Green (John Wiley & Sons)). For example, when R⁴ is diphenylmethyl, acompound represented by a general formula (IX) can be added to anisoleand trifluoro acetic acid at −10 to 10° C., preferably in ice bath. Themixture is stirred at the same temperature for 5 to 30 minutes,preferably 10 to 20 minutes. After the mixture is warmed to 20 to 40°C., the mixture can be stirred for 1 to 4 hours, preferably 2 to 3hours.

The resultant deprotected substance can be reacted with a pyrrolidinederivative synthesized by a method described in Tetrahedron, 27, 2599(1971) through a peptide bond formation similar to method A—first step,thereby obtaining a compound represented by the general formula (VI).

Method B—First Step

The amino group of 3-(4-thiazole)alanine synthesized in accordance witha method described in Synth. Commun., 20, 22, 3507 (1990) and Chem.Pharm. Bull., 38, 1, 103 (1990), is protected by a protecting group foran amino group, such as t-butyloxycarbonyl, benzyloxycarbonyl,9-fluorenylmethoxycarbonyl, phthaloyl, trifluoroacetyl, and the like toobtain a compound represented by a general formula (X). This compoundand a pyrrolidine derivative synthesized by a method described inTetrahedron, 27, 2599 (1971) are subjected to a peptide bond formation.

When t-butyloxycarbonyl is used for the protection, the protectingreaction can be carried out as follows. 3-(4-thiazole)alanine isdissolved in a solvent, such as dioxane, tetrahydrofuran, acetonitrile,and the like. Boc₂O is added to the solution at 0 to 50° C., preferably10 to 30° C., and stirred for 1 to 5 hours, preferably 2 to 4 hours.

A peptide bond formation can be carried out in a manner similar to thatof the above-described method A—First step.

Method B—Second step

A deprotecting reaction for an amino group can be carried out asfollows. When the protecting group is t-butyloxycarbonyl, a compoundrepresented by a general formula (XI) is dissolved in a solvent, such asethyl acetate, and the like. 1 to 4 N hydrochloric acid-ethyl acetatesolution is added to that solution at −10 to 30° C., preferably in ice.The resultant mixture is stirred at the same temperature for 1 to 5hours, preferably 2 to 3 hours.

The resultant deprotected substance can be subjected to a peptide bondformation similar to that of method A—First step, thereby obtaining acompound represented by the general formula (VI).

In the production method, a compound represented by the general formula(V-A) or (V-B) is preferably L-threonine or D-threonine (R¹=methyl).Further, compounds represented by the general formulas (VII-A), (VII-B),(II-A), (II-B), (I-A), (I-B), (III-A), (III-B), (IV-A), (IV-B), and (VI)are also preferably compounds derived from L-threonine or D-threonine.

As R², benzyl is preferable. As R³ and Y, methyl is preferable.

In Examples, the following abbreviations are used.

-   Me:methyl-   Z:benzyloxycarbonyl

EXAMPLES Example 1

Potassium hydroxide (54.77 g) and a compound (1) (L-threonine) (100.0 g)were dissolved in water (1000 ml). To the solution was added potassiumcarbonate (139.23 g). The resultant solution was cooled below 10° C.Toluene (180 ml) solution of Z-Cl (157.5 g) was dropped into thesolution at 10±5° C. for about one hour while the solution wasvigorously stirred. The stirring was further continued for about 1.5hours at the same temperature. Thereafter, the resulting reactionmixture was extracted with toluene (120 ml). The aqueous layer waswashed with toluene (200 ml). Each toluene layer was extracted withwater (50 ml) again. The aqueous layers were combined. To the resultantaqueous layer was added 25% hydrochloric acid (about 294 g) to adjustthe pH to 2.0±0.5, followed by extraction with ethyl acetate (800 ml).The organic layer was washed with 10% brine (400 ml). Each aqueous layerwas extracted with ethyl acetate (200 ml) again. Thereafter, the organiclayers were combined. The organic layer was evaporated. Adding ethylacetate (1000 ml) to the residue and condensing were repeated twice.Further, methanol (500 ml) was added, followed by evaporation.Thereafter methanol was added to adjust the volume to about 440 ml. Tothe resultant methanol solution of compound (2) was dropped thionylchloride (109.9 g) at 10±10° C., followed by stirring at 20±10° C. for2.5 hours. The reaction mixture was dropped into a slurry of sodiumhydrogencarbonate (211.6 g) in water (1320 ml) over about 30 minutes.The resultant slurry was stirred at 5° C. for one hour. Thereafter,crystals were collected by filtration and dried, to obtain 206.3 g ofcompound (3) (yield 92%).

Melting point: 91° C.

¹H NMR (CD₃OD) δ 1.19 (d, J=6.38, 3H), 3.73 (s, 3H), 4.21-4.31 (m, 2H),5.11 (s, 2H), 7.30-7.38 (m, 5H).

Example 2

A solution of a compound (3) (50.0 g) and thionyl chloride (24.48 g) intoluene (250 ml) was stirred at 80° C. for 8 hours and thereafter wascooled to room temperature. The reaction mixture was extracted withwater (150 ml). The aqueous layer was washed with toluene (25 ml). Eachtoluene layer was extracted with water (50 ml) again. Thereafter, theaqueous layers were combined. 36% hydrochloric acid (18.94 g) was addedto the resultant aqueous layer. The aqueous layer was stirred at 80° C.for one hour and thereafter the water was evaporated. Water (100 ml) wasadded to the residue, followed by condensation. Adding acetonitrile (200ml) to the residue and condensing were repeated three times.Acetonitrile was added to adjust the volume to about 50 ml. Theresultant slurry was stirred at 0±5° C. for one hour. Thereafter,crystals were collected by filtration and dried. Thus, 17.4 g ofcompound (5) was obtained (yield 64%).

Melting point: 165° C.

¹H NMR (CD₃OD) δ 1.38 (d, J=6.52, 3H), 4.40 (d, J=8.64, 1H), 4.96 (dq,J=6.54, J=8.66, 1H). [α]_(D) ²⁰ −19.5° (C=1.0, H₂O).

Example 3

A solution of a compound (3) (3.0 g) and thionyl chloride (1.47 g) intoluene (15 ml) was stirred at 80° C. for 8 hours and thereafter wascooled to room temperature. The reaction mixture was extracted withwater (9 ml). The aqueous layer was washed with toluene (1.5 ml). Eachtoluene layer was extracted with water (3 ml) and water (1.5 ml). Theaqueous layers were combined. The resultant aqueous layer was condensed,thereby obtaining 1.48 g of compound (4) as oil (yield 83%).

¹H NMR (CD₃OD) δ 1.31 (d, J=6.48, 3H), 3.79 (s, 3H), 4.46 (d, J=8.52,1H), 4.96 (dq, J=6.48, J=8.52, 1H).

Example 4

Methanol (5 ml) was added to compound (4) (1.0 g) and cooled in ice. 20%aqueous sodium hydroxide solution (2.5 g) was added to the solution,which was in turn stirred in ice bath for 30 minutes. 98% sulfuric acid(0.62 g) was added to the solution. Thereafter, precipitated crystalswere filtered out and the filtrate was condensed. Adding acetonitrile (5ml) to the residue and condensing were repeated four times. Acetonitrile(8 ml) was added to the resultant residue. The solution was dried overanhydrous sodium sulfate (2.2 g). The sodium sulfate was filtered outand the filtrate was condensed. The resultant slurry was stirred in icebath for 30 minutes. Thereafter, crystals were collected by filtrationand dried, thereby obtaining 0.50 g of compound (5) (yield 55%).

Example 5

36% hydrochloric acid (10.5 g) was added to compound (5) (3.00 g). Thesolution was refluxed under stirring for 15 hours. Thereafter, water wasevaporated and water (10 ml) was added to the residue, thereaftercondensing. The residual oil matter was dissolved in water (10 ml).Aqueous lithium hydroxide solution was added to the solution to beadjusted to pH 6, followed by evaporation of water. Methanol (8 ml) wasadded to the resultant solid, followed by stirring at room temperaturefor one hour, thereafter subjected to filtration and dried. Thus, 2.25 gof compound (6) (L-allo-threonine) was obtained (yield 91%).

¹H NMR (D₂O) δ 1.20 (d, J=6.30, 3H), 3.83 (d, J=3.90, 1H), 4.36 (dq,J=3.90, J=6.60, 1H). [α]_(D) ²⁰ +9.07° (C=2.0, H₂O).

Industrial Applicability

According to the production method of the present invention,oxo-oxazoline derivatives and alloamino acid derivatives can be producedin a stereoselective and inexpensive manner.

1. A method for production of a compound represented by the generalformula (I-A) or the general formula (I-B), comprising the step ofprotecting the amino group of a compound represented by the generalformula (V-A) or the general formula (V-B) with R²OC(═O)—, wherein R² isa lower alkyl, an optionally substituted aralkyl, or an optionallysubstituted heteroarylalkyl, esterifying the carboxyl group thereof, andtreating with thionyl chloride as follows:

wherein R¹ is an optionally substituted lower alkyl, an optionallysubstituted aryl, an alkynyl, or an optionally substituted heteroaryland R³ is a lower alkyl.